Molecular genetic manipulations in mice provide some of the most sophisticated means for investigating the neurobiology, psychophysiology and psychopharmacology of abused drugs. Our laboratory is specifically interesting in the integration of molecular biology, behavior genetics and behavior pharmacology. To date, our laboratory has examined intravenous opioid self-administration behavior in two inbred (C57, BALB), recombinant inbred (mu-deficient CXBK, opiate-rich CXBH) and transgenic lines of mice (overexpressing superoxide-dismutase, overexpressing mu-opiate receptor). These mice are some of the most divergent lines available in terms of CNS opiate receptor concentration. For example, the recent insertion of the Cu/Zn-superoxide dismutase (SOD) transgene results in a 5.7 fold increase in brain CuZnSOD-activity and a significant specific increase in CNS mu-opiate receptors in dopaminergic regions. Increased mu-opiate binding is observed in the shell versus core of the nucleus accumbens, substantia nigra pars compacta and the ventral tegmental area. Given the functionally relevant increase in mu-receptors and the proposed importance of the shell versus core of the nucleus accumbens in drug-reinforced behavior our interest was to assess operant i.v. opioid-reinforced behavior in these transgenic mice. The results of this study demonstrate significantly greater amounts of morphine self-administration behavior in the SOD mice versus the CD mice. SOD transgenic mice self-administered an average of 3.1-fold greater amounts of drug than the host CD mice across all three doses. These data demonstrate a significant effect of the Cu/Zn transgene on opioid-reinforced behavior and provide additional support for the relative importance of subdivisions within the nucleus accumbens. Complimentary studies in the transgenic THM mice yield similar results consistent with the positive relationship between opiate-receptor concentration and self-administration behavior. However, studies in the inbred and recombinant strains suggest a more complicated picture in which region-specific changes in opiate receptor concentration underly both the potency and efficacy of morphine as a reinforcer.